2-oxoindolines

ABSTRACT

3-PHENACYLIDENE-2-OXOIDOLINE - 7 - CARBOXYLIC ACIDS AND ESTERS, PREPARED BY CONVERTING 2,3-DIOXOINDOLINE-7CARBOXYLIC ACIDS TO 3-HYDROXY-3 PHENACYL-2-OXO COMPOUNDS AND SUBSEQUENT DEHYDRATION. THE 3-PHENACYLIDENE COMPOUNDS ARE REDUCED TO THE 3-PHENACYL COMPOUNDS AND THEN RING-CLOSED WITH HYDRAZONE TO GIVE 3-PEHNYLPYRIDAZINOINDOLES, 2-OXOINDOLINE-7-CARBOXYLIC ACIDS ARE PREPARED BY STEPWISE REDUCTION OF THE 2-3-DIOXO COMPOUNDS. CERTAIN OF THE COMPOUNDS HAVE ANTIINFLAMMATORY ACTIVITY.

United States Patent G1 he? 3,631,178 Patented Dec. 28, 1971 3,631,178Z-OXODIDOLINES Kenneth G. Holden, Haddonfield, N.J., assignor to SmithKline 8: French Laboratories, Philadelphia, Pa. No Drawing. Originalapplication Apr. 18, 1967, Ser. No. 631,619, now Patent No. 3,519,592,dated July 7, 1970. Divided and this application Apr. 21, 1970, Ser.

Int. Cl. C07d 27/40 US. Cl. 260-325 4 Claims 10 ABSTRACT OF THEDISCLOSURE 3-phenacylidene 2 ox oindoline 7 carboxylic acids and esters,prepared by converting 2,3-dioxoindoline-7- carboxylic acids to3-hydroXy-3-phenacyl-2-0Xo compounds and subsequent dehydration. The3-phenacylidene compounds are reduced to the 3-phenacyl compounds andthen ring-closed with hydrazine to give 3-pehnylpyridazinoindoles,2-oxoindoline-7-carboXylic acids are prepared by stepwise reduction ofthe 2-3-dioxo compounds. Certain of the compounds have antiinflammatoryactivity.

This application is a division of copending application Ser. No.631,619, filed Apr. 18, 1967, now US. Pat. No. 3,519,592.

This invention relates to heterocyclic compounds having utility asantiinflamrnatory agents or as intermediates therefor. In particular,the invention relates to indolecarboxylic acid andpyridazinoindolecarboxylic acid compounds.

One group of compounds within the scope of the invention is representedby the following formula:

wherein R is hydrogen or lower alkyl, and X is hydrogen, lower alkyl,lower alkoxy, chloro, bromo, fluoro, or trifluoromethyl.

A second group of compounds within the scope of the invention isrepresented by structural Formula II.

wherein R and X are as defined above.

A third group of compounds within the scope of the invention isrepresented by structural Formula III.

N \N N/ ROOG wherein R and X are as defined above.

A fourth group of compounds within the scope of the invention isrepresented by structural Formula IV.

OQE EQ wherein R and X are as defined above.

A fifth group of compounds within the scope of the invention isrepresented by structural Formula V.

wherein R is as defined above.

A final group of compounds within the scope of the invention isrepresented by structural Formula VI.

OH (I) X Q CH l The 3 hydroxy-3phenacyl-2-oxo-7-indolinecarboxylic acidsand esters of Formula II are prepared by condensing the correspondingisatincarboxylic acid or ester VII with the appropriate acetophenone inthe presence of a base such as diethylamine. The reaction is preferablyconducted in refluxing alcohol. The phenacylidene compounds of Formula Iare prepared by dehydrating the phenacyl compounds of Formula II usingglacial acetic acid containing a small amount of hydrochloric acid onthe steam bath. The phenacyl compounds of Formula IV are obtained byreduction of the phenacylidene compounds of Formula I with sodiumhydrosulfite in aqueous alcohol. The3-phenyl-9H-pyridazino[3,4-b]indoles of Formula III are prepared bytreating the phenacyl compounds IV with hydrazine in the presence ofoxygen and an acid such as acetic acid. The 3-hydroxy-2-oxo compounds ofFormula VI are prepared by reducing the 3-oxo group of the startingisatin compounds VII with sodium hydrosulfite. Reduction of this3-hydroxy group to give the 2-oxo compounds of Formula V is accomplishedwith sodium and lead.

The carboxylic acid compounds (R=H) are prepared either by using acarboxylic acid as starting material or by hydrolyzing an ester. Theesters in turn may be prepared either by using the corresponding estersas starting material or by esterifying a carboxylic acid product.

The compounds of Formulas I, III, and V possess antiinflammatoryactivity. Among the preferred compounds are 3 (p fluorophenacylidene) 2oxoindoline 7- carboxylic acid, 3 (rn fluorophenacylidene) 2 oxoindoline7 carboxylic acid, 3 (m trifluoromethylphenacylidene) 2 oxoindoline 7carboxylic acid, 3- phenyl 9H pyridazino[3,4 b]indole 8 carboxylic acid,and 2-oxindoline-7-carboxylic acid, which possess antiinflammatoryactivity in rats when administered orally and subcutaneously in doses of40-50 mg./kg.

These compounds are formulated for use in inflammatory conditions bycombining them either in the form of the free bases or zwitterions,their pharmaceutically acceptable acid addition salts, when such exist,or their alkali metal or amine salts with standard pharmaceuticalexcipients according to conventional practice in order to preparetablets, capsules, injectables, and ointments.

The compounds of Formulas II, IV, and VI are useful as intermediates forpreparing the antiinflammatory agents. The 3-hydroxy-3-phenacylcompounds of Formula II are useful for preparing both the3-phenacylidene compounds of Formula I and the pyridazinoindolecompounds of Formula III, while the 3-phenacyl compounds of Formula IVare useful for preparing the pyridazinoindole compounds. The3-hydroxy-2-oxoindolines of Formula VI O N I H (H) X "C? are useful forpreparing the 2-oxoindolines of Formula V.

The following examples are intended to illustrate the preparation of thecompounds of the invention, but are not to be construed as limiting thescope thereof. Temperatures stated are in degrees centigrade.

EXAMPLE 1 3-hydroxy-3-phenacyl-2-oxoindolinc-7-carboxylic acid methylester A suspension of 5.0 g. (26 mmoles) of methyl2,3-dioxoindoline-7-carboxylate in ml. of boiling ethanol is treatedwith 3.7 g. (31 mmoles) of acetophenone and 15 drops of diethylamine.Boiling is continued for 1 hour after complete solution is achieved andthe solution is then allowed to stand overnight. The mixture is cooledand the resulting precipitate filtered off and Washed with ether to givethe title product, M.P. 157-160". A second crop is obtainable from themother liquor. The compound is recrystallized from ethanol and melts at15 8-160".

EXAMPLE 2 3-hydroxy-3-phenacyl-2-oxoindoline-7-carboxylic acid To aboiling suspension of 2 g. (11.15 mmoles) of 2,3-dioxoindoline-7-carboxylic acid in 60 ml. of ethanol is added 1.5 g.(12.5 mmoles) of acetophenone and 1.3 ml. (0.92 g., 12.7 mmoles) ofdiethylamine. The solution is allowed to stand overnight, concentratedto about onehalf volume, cooled, and filtered. The dried precipitate ofthe diethylamine salt of the product is recrystallized frommethanol-ethyl acetate and melts at 183 dec.

EXAMPLE 3 3-hydroxy-3 (m-fluorophenacyl) -2-oxoindoline-7- carboxylicacid A mixture of 5.72 g. (30 mmoles) of 2,3-dioxoindoline- 7-carboxy1icacid, 3.6 ml. (2.55 g., 35 mmoles) of diethylamine, and 4.14 g. (30mmoles) of m-fiuoroacetophenone in 100 ml. of absolute ethanol is heateduntil solution is complete and then allowed to stand overnight. Themixture is then cooled and filtered to give the title product, M.P.158160 dec.

EXAMPLE 4 3 -hydroxy-3- p-fluorophenacyl -2-oxoindoline-7- carboxylicacid Use of p-fluoroacetophenone in the procedure of Example 3 insteadof m-fluoroacetophenone results in the formation of the title product,M.P. 173177 dec.

EXAMPLE 3-hydroxy-3- (m-trifluoromethylphenacyl -2-oxoindoline-7-carboxylic acid Use of 5.64 g. (30 mmoles) ofm-trifluoromethylacetophenone in the procedure of Example 3 instead ofmfluoroacetophenone results in the formation of the title product, M.P.103-106. The product is isolated by evaporating the ethanol, dissolvingthe residue in hot ethyl acetate, treating with charcoal, filtering, andallowing the product to crystallize from the filtrate.

EXAMPLE 6 3-phenacylidene-2-oxoindoline-7-carboxylic acid methyl ester Asuspension of 6.8 g. (22 mmoles) of 3-hydroxy-3-phenacyl-2-oxoindoline-7-carboxylic acid methyl ester in 35 ml. ofglacial acetic caid containing 1 ml. of conc. HCl is heated on the steambath. After a few minutes solution is complete. Upon continued heating aprecipitate forms, the mixture is diluted with 35 ml. of 95% ethanol,cooled and filtered. The recovered precipitate of the title product isrecrystallized from ethanol; 192-193.

EXAMPLE 7 3-phenacylidene-2-oxoindoline-7-carboxylic acid A suspensionof 5.48 g. (13.6 mmoles) of 3-hydroxy-3-phenacyl-2-oxoindoline-7-carboxylic acid in 50 ml. of glacial aceticacid containing 3 ml. (36 mmoles) of conc. HCl is heated on the steambath with stirring. After 30 minutes, the thick mixture is diluted withalcohol and water, and filtered. Recrystallization from ethanol-watergives the title product, M.P. 253256 dec.

EXAMPLE 8 3-(m-fluorophenacylidene)-2-oxoindoline-7-carboxylic acid Asuspension of 7.7 g. (19.2 mmoles) of 3-hydroxy-3-(m-fluorophenacyl-2-oxoindoline-7-carboxylic acid in 100 ml. of glacialacetic acid is treated with ml. of conc. HCl and heated to boiling withstirring. When the reaction has been indicated by thin layerchromatography to be complete, the mixture is diluted to 200 ml. withwater and ethanol, cooled, and filtered. Recrystallization of therecovered precipitate from ethanol-ethyl acetate gives the titleproduct, M.P. 253-255 EXAMPLE 9 3- (p-fluorophenacylidene-2-oxoindoline-7-carboxylic acid Use of 8.7 g. (21.6 mmoles) of3-hydroxy-3-(p-fiuorophenacyl)-2-oxoindoline-7-carboxylic acid in theprocedure of Example 8 instead of the m-fiuoro compound results in theformation of the title product, recrystallized from ethanol-ethylacetate; M.P. 263-268".

EXAMPLE 10 3 (m trifiuoromethylphenacylidene) 2-oxoindoline-7-carboxylic acid Use of 7.1 g. (15.7 mmoles) of3-hydroxy-3-(m-trifluoromethylphenacyl)-2-oxoindoline-7-carboxylic acidin the procedure of Example 8 instead of the m-fluorophenacyl compoundresults in the formation of the title product, recrystallized from ethylacetate; M.P. 235-237 EXAMPLE 11 3-phenacyl-2-oxoindoline-7-carboxylicacid A suspension of 11.2 g. (38.2 mmoles) of3-phenacylidene-Z-oxoindoline-7-carboxylic acid in 150 ml. of alcohol isheated with stirring and treated with 15 g. of Na S O in 50 ml. ofwater. Heating is continued until most of the color is dissipated andthe mixture is then allowed to stir on a warm hot plate for 45 minutes.The mixture is diluted with water, seeded, and allowed to standovernight in the refrigerator. The resulting precipitate is filteredoff, dried, and recrystallized from ethanol-water to give the titleproduct, M.P. 243-246".

EXAMPLE 12 Use of 3 phenacylidene 2-oxoindoline-7-carboxylic acid methylester, 3-(m-fiuorophenacylidene)-2-oxoindoline-7-carboxylic acid,3-(p-fluorophenacylidene)-2- oxoindoline-7- carboxylic acid, or 3-(m-trifluoromethylphenacylidene)-2-oxoindoline-7-carboxylic acid asstarting material in the procedure of Example 11 results in theformation of 3-phenacyl-2-oxoindoline-7-carboxylic acid methyl ester,3-(m-fiuorophenacyl)-2-oxoindoline-7-carboxylic acid,3-(p-fluorophenacyl)-2-oxoindoline-7-carboxylic acid, or3-(m-trifluoromethylphenacyl)-2-oxoindoline-7-carboxylic acid,respectively.

EXAMPLE 13 3-phenyl-9H-pyridazino 3,4-b indole-S-carboxylic acid Asuspension of 6 g. (20.3 mmoles) of 3-phenacyl-2-oxoindoline-7-carboxylic acid in 50 ml. of glacial acetic acid is heatedand stirred while 3 ml. of hydrazine hydrate is added. The mixture isheated to near boiling and stirred for 2 hours, diluted with water,cooled, and filtered. The recovered precipitate is recrystallized fromdimethylformamide-water to give the title product, M.P. 282-284".

EXAMPLE 14 Use of 3 phenacyl 2-oxoindoline-7-carboxylic acid methylester, 3- (mfluorophenacyl -2-oxoindoline-7-carboxylic acid,3-(p-fluorophenacyl)-2-oxoindoline-7-carboxylic acid, or3-(m-trifiuoromethylphenacyl)-2-oxoindoline-7-carboxylic acid asstarting material in the proceduce of Example 13 results in theformation of 3-phenyl- 9H pyridazin0[3,4-b]indole 8-carboxylic acidmethyl ester, 3 (m fluorophenyl)-9H-pyridazino[3,4-b]indole-8-carb0xylic acid, 3-p-fluoropheny1) -9H-pyridazino[3 ,4-b]indole-8-carboxylic acid, or 3-(m-trifiuoromethylphenyl)-9H-pyridazino[3,4-b]indole-S-carboxylic acid, respectively.

EXAMPLE 15 3-hydroxy-2-oxoindoline-7-carboxylic acid A suspension of19.0 g. of 2,3-dioxoindoline-7-carboxylic acid in 200 ml. of hot wateris stirred and heated to boiling while 34 g. of Na S O is added inportions. The mixture is boiled for 20 minutes, cooled, and thencontinuously extracted with ether for 3 days. Evaporation of the etherand recrystallization of the residue from methanol gives the titleproduct, M.P. 203-207.

Use of the methyl ester of the above starting material results in theformation of the methyl ester of the product.

EXAMPLE l6 2-oxoindoline-7-carboxylic acid A solution of 3.0 g. (15.5mmoles) of 3-hydroxy-2- oxoindoline-7-carboxylic acid in 30 ml. of watercontaining 2.0 g. (23.8 mmoles) of NaHCO is stirred at 0 while a streamof CO is bubbled in, and 10 g. of Na-Pb (9.6% Na; 0.96 g. of Na, 42mmoles) is added in several portions over a 2 hour period. After about 3hours, when thin layer chromatography indicates the reaction to becomplete, the mixture is filtered, the filtrate acidified, and theresulting precipitate collected. Recrystallization from methanol givesthe title product, M.P. 244-246.

Use of the methyl ester gives the corresponding ester product.

EXAMPLE 17 When the following acetophenones are used as startingmaterials in the procedure of Example 2 in place of acetophenone, thecorresponding listed 3-hydroxy-3- phenacyl compounds are obtained.

When the above listed 3-hydroxy-3-phenacyl compounds are dehydratedaccording to the procedure of Example 7, the following 3-phenacylidenecompounds are obtained, respectively.

3-(o-chlorophenacylidene)-2-oxoindoline-7-carboxylic acid3-(m-bromophenacylidene)-2-oxoindoline-7-carboxylic acid3-(p-methylphenacylidene)-2-oxoindoline-7-carboxylic acid3-(o-butylphenacylidene)-2-oxoindoline-7-carboxylic acid3-,(p-ethoxyphenacylidene -2-oxoindoline-7-carb oxylic acid When theabove listed 3-phenacylidene compounds are reduced with Na S O accordingto the procedure of Example 11, the following 3-phenacyl compounds areobtained, respectively.

3- (o-chlorophenacyl -2-oxoindoline-7-carboxylic acid3-(m-bromophenacyl) -2-oxoindoline-7-carboxylic acid 3-(p-methylphenacyl (-2-oxoindoline-7-carboxylic acid 3-.(o-butylphenacyl) -2-oXoindoline-7-carboxylic acid 3- p-ethoxyphenacyl)-2-oxoindoline-7-carboxy1ic acid When the above listed 3-phenacy1compounds are com densed with hydrazine hydrate according to theprocedure of Example 13, the following pyridazinoindolecarboxylic acidsare obtained, respectively.

3-(o-ch10r0phenyl) -9H-pyridazino 3,4b] indole-8- carboxylic acid3-,(m-bromophenyl)-9H-pyridazino[3,4-b1indole-8- carboxylic acid 3-(p-tolyl -9H-pyridazino 3,4-b] indole-8-carboxylic acid 3-(o-butylphenyl -9H-pyridazino 3,4-b] indole-8- carboxylic acid 3-(p-ethoxyphenyl) -9H-pyridazino 3,4-b] indole-8- carboxylic acidEsterification of any of the above carboxylic acid products withmethanol, ethanol, propanol, or butanol, using acid catalysis withhydrogen chloride or sulfuric acid, results in the formation of thecorresponding methyl, ethyl, propyl, or butyl ester.

When the above pyridazinoinodole carboxylic acids or esters aredissolved or suspended in anhydrous alcohols, acetone, or ether, andhydrogen chloride, maleic acid, or a similar pharmaceutically acceptableacid added, as such or as an ethereal, acetone, or alcoholic solution,the corresponding salt is obtained.

Alkali metal salts such as sodium or potassium, or amine salts such asthe ammonium, triethylammonium salts, etc. are prepared by treating afree acid compound in solution with the alkali metal hydroxide,bicarbonate, or carbonate, or with ammonia, triethylamine, or otheramine.

I claim:

1. A compound of the formula wherein R is hydrogen or lower alkyl.

2. A compound as claimed in claim 1, being the compound3-hydroxy-2-oxoindoline-7-carboxylic acid.

3. A compound of the formula wherein R is hydrogen or lower alkyl.

4. A compound as claimed in claim 3, being the conipound2-oxoindoline-7-carboxylic acid.

References Cited UNITED STATES PATENTS 2,872,372 2/1959 Hull 260-240 XALEX MAZEL, Primary Examiner JOSEPH A. NARCAVAGE, Assistant Examiner US.Cl. X.R.

